CN116283971A - 含稠合杂环结构的吲哚啉类化合物及其制备方法和应用 - Google Patents
含稠合杂环结构的吲哚啉类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一类含稠合杂环结构的吲哚啉类化合物及其制备方法和应用，属于医药领域，具体公开通式I所示的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，它们的制备方法和其在制备治疗与PD‑1/PD‑L1蛋白/蛋白相互作用有关的疾病的药物中的应用。本发明涉及化合物对PD‑1/PD‑L1蛋白/蛋白相互作用具有高水平的抑制活性，所述含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐可用于制备治疗与PD‑1/PD‑L1信号通路异常有关的疾病如癌症、感染性疾病、自身免疫性疾病的药物。
Description
技术领域
本发明涉及一类含稠合杂环结构的吲哚啉类化合物及其制备方法和应用，属于医药领域。
背景技术
免疫治疗是近年来肿瘤治疗的热点领域，于2013年被《Science》评为十大科学突破之首。程序性死亡受体1(programmed death1,PD-1)是T细胞表面受体，当其与程序性死亡配体1(programmed cell death-ligand 1，PD-L1)结合时产生负性免疫调节信号，从而抑制T细胞活化、增殖以及白细胞介素2(IL-2)、干扰素-γ(IFN-γ)等细胞因子的释放(Eur.J.Immunol.2002,32(3):634-643.)。大量研究表明，机体内的肿瘤微环境会诱导浸润的T细胞中PD-1表达上调，同时肿瘤细胞高表达PD-L1，导致PD-1/PD-L1介导的信号通路持续激活，肿瘤特异性CD8+T细胞功能被抑制以至于不能识别或杀伤肿瘤细胞，即肿瘤细胞实现免疫逃逸。因此靶向阻断PD-1/PD-L1蛋白/蛋白相互作用，可以恢复T细胞功能，使其重新识别并杀伤肿瘤细胞。
基于PD-1/PD-L1的免疫疗法备受瞩目，2014年以来，先后有10余种靶向PD-1/PD-L1的单克隆抗体药物获批上市，目前已被批准上市的PD-1/PD-L1单抗包括默沙东的Pembrolizumab、百时美施贵宝的Nivolumab、默克的Avelumab、阿斯利康的Durvalumab、罗氏的Atezolizumab等。上述单抗已在多种肿瘤类型的治疗中显示出明显疗效，被批准的适应症包括黑色素瘤、非小细胞肺癌、胃癌、尿路上皮癌等。随着临床研究的开展，单抗药物有望在更多的适应症中实现突破。
虽然单抗药物在临床治疗中显示出优势，但也存在明显的缺陷如制备和纯化困难、生产成本高昂；易被蛋白酶分解，半衰期短；不能口服，只能注射给药；单抗的免疫原性导致严重的毒副作用等。相比于生物大分子药物，小分子化合物经化学修饰后药物代谢动力学性质可控，另外在生产工艺、给药方式等方面也具有更大的探索与优化空间。开发靶向PD-1/PD-L1信号通路的小分子抑制剂是实现免疫治疗的可行性的选择。
发明内容
本发明提供一系列结构新颖的含稠合杂环结构的吲哚啉类化合物。研究表明，该类化合物可以显著抑制PD-1/PD-L1蛋白/蛋白相互作用。本发明涉及通式I所示的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，它们的制备方法以及含有所述化合物的药物组合物，其中取代基R1、R2、R3、X、Y的含义均在说明书中阐述。本发明涉及化合物对PD-1/PD-L1蛋白/蛋白相互作用具有高水平的抑制活性，所述含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐可用于制备治疗与PD-1/PD-L1信号通路异常有关的疾病如癌症、感染性疾病、自身免疫性疾病的药物。
本发明涉及通式I所示的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，
其中，
R1选自苯基或
X、Y各自独立地选自CH或N；
R2、R3各自独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1C4)烷基、氨基磺酰基(C1C4)烷基、甲磺酰氨基(C1-C4)烷基、氨基磺酰氨基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基，含有1-3个选自N、O或S原子的4-7元杂环烷基；其中，所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰氨基(C1-C4)烷基、氨基磺酰氨基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基，含有1-3个选自N、O或S原子的4-7元杂环烷基可任选被1-3个R4取代；
或者R2、R3和与它们相连的氮原子一起形成一个3-7元的含氮杂环；所述的含氮杂环含有1-3个选自N、O或S的杂原子；所述的含氮杂环可任选被1-3个R5取代，环上碳原子可被氧代；
R4选自氢、卤素、羟基、羧基、氨基、(C1-C4)烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C1-C4)酰基；
R5选自氢、羟基、羧基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧甲酰基、羟基(C1-C4)烷基；
本发明优选涉及通式I的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，其中，
R1选自苯基或
X、Y各自独立地选自CH或N；
R2、R3各自独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰氨基(C1-C4)烷基、氨基磺酰氨基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基，含有1-3个选自N、O或S原子的4-6元杂环烷基；其中，所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、羧基(C1-C4)烷基、(C1C4)烷氧甲酰基(C1C4)烷基，含有1-3个选自N、O或S原子的4-6元杂环烷基可任选被1-3个R4取代；
或者R2、R3和与它们相连的氮原子一起形成一个4-6元的含氮杂环；所述的含氮杂环含有1-3个选自N、O的杂原子；所述的含氮杂环可任选被1-3个R5取代，环上碳原子可被氧代；
R4选自氢、羟基、羧基、氨基、(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C1-C4)酰基；
R5选自氢、羟基、羧基、(C1-C4)烷基、(C1-C4)烷氧基、羟基(C1-C4)烷基；
本发明更加优选涉及通式I的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，其中，
R1选自苯基或
X、Y各自独立地选自CH或N；
本发明通式I的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐优选自以下化合物，但这些化合物并不意味着对本发明的任何限制：
此外，本发明还包括本发明化合物的前药。本发明化合物的前药是通式I的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
以上所述的通式I的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，所述的药学上可接受的盐包括与无机酸、有机酸、碱金属离子形成的盐；所述的无机酸选自：盐酸、氢溴酸、氢氟酸、硫酸、磷酸；所述的有机酸选自：琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸或对甲苯磺酸；所述的碱金属离子选自锂离子、钠离子或钾离子。
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“含氮杂环”是指含有氮原子的单环或多环的环状体系，环状体系是非芳香性或芳香性的；“”代表取代基连接处。
本发明可以含有上述通式I的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐作为活性成分，与药学上可接受的载体或赋形剂混合制备成组合物。所述载体或赋形剂包括本领域公知的稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂等。稀释剂包括但不限于淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、磷酸氢钙等；湿润剂包括但不限于水、乙醇、异丙醇等；粘合剂包括但不限于淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、羟丙基甲基纤维素、乙基纤维素、聚乙二醇等；崩解剂包括但不限于干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、十二烷基磺酸钠等；润滑剂和助流剂包括但不限于滑石粉、二氧化硅、聚乙二醇等。
本发明的药用组合物可配制成若干种剂型，所述剂型包括但不限于注射剂、片剂、胶囊剂等。
本发明的含稠合杂环结构的吲哚啉类类化合物及其立体异构体以及药学上可接受的盐可以与其他活性成分组合使用，从而达到更优的治疗效果。
本发明还提供了通式I的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐在制备预防和/或治疗与PD-1/PD-L1信号通路有关疾病的药物中的应用。所述的与PD-1/PD-L1信号通路有关的疾病选自癌症、感染性疾病、自身免疫性疾病。所述的癌症选自淋巴瘤、非小细胞肺癌、小细胞肺癌、头颈部细胞癌、神经胶质瘤、成神经细胞瘤、肺鳞癌、肺腺癌、膀胱癌、胃癌、结肠癌、大肠癌、肾癌、胆管癌、胃癌、食管鳞癌、卵巢癌、胰腺癌、乳腺癌、前列腺癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、皮肤癌、上皮细胞癌、白血病和宫颈癌；所述的感染性疾病选自细菌感染、病毒感染；所述的自身免疫性疾病选自器官特异性、系统性自身免疫病。其中，所述器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、溃疡性结肠炎、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿性关节炎、系统性红斑狼疮、系统性血管炎、自身免疫性溶血性贫血。
本发明的积极进步效果在于：本发明的含稠合杂环结构的吲哚啉类化合物具有新颖的化学结构，大多数化合物在体外生物学活性研究中对PD-1/PD-L1相互作用具有显著的抑制活性，代表性化合物在体内生物学活性研究中可显著抑制肿瘤生长，所述化合物可用于癌症等多种疾病的治疗和预防。
附图说明
图1为实施例2化合物在过表达PD-L1的LLC肿瘤动物模型中体内药效学结果。
具体实施方式
下面的合成路线概括并描述了本发明的通式I衍生物的制备，所有的原料都是通过这些流程中描述的方式、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的衍生物都是通过这些流程中描述的方法或通过与其类似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些流程中应用的全部可变因数如权利要求中的定义。
(a)以4-溴-1H-吲哚为原料，与苯硼酸或1,4-苯并二噁烷-6-硼酸频那醇酯通过Suzuki-Miyaura偶联反应制得中间体2；
(b)中间体2在还原剂如氰基硼氢化钠作用下制得中间体3；
(c)以中间体3为原料，在酸催化下与稠合杂环的氯代物反应制得中间体4；
(d)以中间体4为原料，与乙烯基硼酸频哪醇酯或三丁基乙烯基锡试剂通过偶联反应制得中间体5；
(e)以中间体5为原料，在锇试剂及氧化剂的作用下制得中间体6；
(f)以中间体6为起始原料，与胺类化合物缩合及氰基硼氢化钠或三乙酰氧基硼氢化钠作用下制得通式I中的目标化合物。；
所述的R1、R2、R3、X、Y的定义如权利要求所述。本发明的具有通式I的含有稠合杂环结构的吲哚啉类化合物均可按照上述反应路线描述的方法或类似的方法制备得到。
下文中提供的实施例进一步阐明和举例说明本发明化合物及其制备方法。应当理解，下述实例和制备例的范围并不以任何方式限制本发明的范围。
实施例1：2-(((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙-1-醇(化合物I-1)
步骤1：4-苯基-1H-吲哚
室温下，将4-溴-1H-吲哚(10g,51.5mmol)、苯硼酸(8.1g,67.0mmol)、Pd(dppf)Cl2(1.1g,1.54mmol)、碳酸钾(17.7g,128.7mmol)依次加入到1,4-二氧六环(80mL)和水(20mL)的混合溶液中，在N2保护下90℃反应3h。反应完成后，将反应液冷却至室温，垫硅藻土抽滤，滤饼用乙酸乙酯洗涤，浓缩滤液，加水并用乙酸乙酯萃取，有机相用无水硫酸钠干燥，抽滤，浓缩滤液并通过柱层析纯化，制得白色固体8.94g，收率90.1％。1H NMR(600MHz,DMSO-d6)δ11.27(s,1H),7.67(d,J＝7.3Hz,2H),7.49(t,J＝7.7Hz,2H),7.42(t,J＝5.9Hz,2H),7.37(t,J＝7.4Hz,1H),7.18(t,J＝7.6Hz,1H),7.08(d,J＝7.1Hz,1H),6.55(s,1H).ESI-MS m/z:194.2[M+H]+。
步骤2：4-苯基吲哚啉
室温下将4-苯基-1H-吲哚啉(8g,41.4mmol)加入到30mL冰醋酸中，然后于冰浴下缓慢加入氰基硼氢化钠(7.8g,124.2mmol)，加毕，室温反应2h。反应完成后，将反应液倒入200mL水中，冰浴下用40％ NaOH溶液调节pH至9-10，乙酸乙酯(200mL×3)萃取，有机层用饱和食盐水洗涤，减压浓缩，柱层析分离得白色固体7.23g，收率89.5％。1H NMR(600MHz,DMSO-d6)δ7.47–7.40(m,4H),7.36–7.29(m,1H),7.00(t,J＝7.7Hz,1H),6.59(d,J＝7.1Hz,1H),6.51(d,J＝7.7Hz,1H),5.59(s,1H),3.39(t,J＝8.4Hz,2H),2.97(t,J＝8.4Hz,2H).ESI-MS m/z:196.1[M+H]+。
步骤3：3-氨基-5-溴吡啶-2-甲腈
冰浴下，将2-氰基-3-硝基-5-溴吡啶(10g,43.9mmol)的冰醋酸(60mL)溶液，缓慢地加入到铁粉(13.6g,241.2mmol)的冰醋酸悬浊液中，加毕，室温下反应30min。反应完成后，向反应液中加入200mL的乙酸乙酯，垫硅藻土多次抽滤至滤液为澄清红色溶液，浓缩滤液，残留物用乙酸乙酯稀释，用1M NaOH溶液洗涤至有机相为淡黄色，蒸干有机相得黄色固体8.07g，收率93.8％。1H NMR(600MHz,DMSO-d6)δ7.93(d,J＝2.1Hz,1H),7.45(d,J＝2.0Hz,1H),6.54(s,2H).ESI-MS m/z:198.0[M+H]+。
步骤4：7-溴吡啶并[3,2-d]嘧啶-4(3H)-酮
将3-氨基-5-溴吡啶-2-甲腈(8.07g,40.7mmol)、乙酸钠(6.7g,81.5mmol)依次加入到80mL甲酸中，100℃反应10h。反应完成后，将反应液冷却至室温，浓缩反应液，将浓缩物加入到100mL得2M NaOH溶液中，搅拌10min，抽滤，将所得固体加入到100mL的2MHCl溶液中，搅拌30min，抽滤干燥得土黄色固体6.7g，收率69.0％。ESI-MS m/z:226.0[M+H]+。
步骤5：7-溴-4-氯吡啶并[3,2-d]嘧啶
将7-溴吡啶并[3,2-d]嘧啶-4(3H)-酮(6.7g,29.8mmol)、DIPEA(13.9g,107.2mmol)溶于70mL的干燥甲苯中，冰浴下缓慢滴加POCl3(6.33g,41.7mml)，加毕，90℃反应1h。反应完成后，将反应液倒入150mL水中，乙酸乙酯(100mL×3)萃取，用无水硫酸钠干燥有机相，抽滤，蒸干滤液，将所得固体用乙醚打浆纯化得黄色固体4.23g，收率58.5％。1HNMR(600MHz,Chloroform-d)δ9.07(d,J＝2.1Hz,1H),9.06(s,1H),8.52(d,J＝2.1Hz,1H).ESI-MS m/z:243.9[M+H]+。
步骤6：7-溴-4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶
将4-苯基吲哚啉(3g,15.4mmol)、7-溴-4-氯吡啶并[3,2-d]嘧啶(3.73g,15.4mmol)加入到30mL异丙醇中，再加入1滴浓盐酸，60℃反应1h，有大量黄色固体析出。反应完成后，将反应液冷却至室温，抽滤，滤饼用乙醚洗涤，干燥得黄色固体5.51g，收率89.2％。1H NMR(600MHz,DMSO-d6)δ8.98(d,J＝2.3Hz,1H),8.75(s,1H),8.53(d,J＝2.3Hz,1H),8.46(d,J＝8.2Hz,1H),7.55–7.52(m,2H),7.52–7.48(m,2H),7.43–7.37(m,2H),7.16(dd,J＝7.6,1.0Hz,1H),4.87(t,J＝8.1Hz,2H),3.29(t,J＝8.0Hz,2H).ESI-MS m/z:403.1[M+H]+。
步骤7：4-(4-苯基吲哚啉-1-基)7-乙烯基吡啶并[3,2-d]嘧啶
将7-溴-4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶(5.5g,13.7mmol)溶于40mLDMF与5mL水的混合溶液中，随后依次加入乙烯基硼酸频哪醇酯(2.53g,16.4mmol)、碳酸钾(5.67g,41.0mmol)及Pd(PPh3)4(0.79g,0.68mmol)，在N2保护下100℃反应2h。反应完成后，将反应液冷却至室温，垫硅藻土抽滤除去不溶物，将滤液倒入300mL水中，乙酸乙酯(200mL×3)萃取，浓缩有机相并用柱层析纯化得黄色固体4.07g，收率85.1％。1H NMR(600MHz,Chloroform-d)δ8.81(d,J＝2.2Hz,1H),8.70(s,1H),8.36(d,J＝8.2Hz,1H),8.00(d,J＝2.1Hz,1H),7.40–7.37(m,4H),7.33–7.27(m,2H),7.05(dd,J＝7.6,1.0Hz,1H),6.81(dd,J＝17.7,11.0Hz,1H),6.01(d,J＝17.7Hz,1H),5.53(d,J＝11.0Hz,1H),4.86(t,J＝8.1Hz,2H),3.21(t,J＝8.1Hz,2H).ESI-MS m/z:351.1[M+H]+。
步骤8：4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-甲醛
将中间体4-(4-苯基吲哚啉-1-基)7-乙烯基吡啶并[3,2-d]嘧啶(4g,11.4mmol)溶于1,4-二氧六环(40mL)和水(10mL)的混合溶液中，随后加入K2OsO4·2H2O(0.34g,0.91mmol)，室温下搅拌15min，加入NaIO4(9.77g,45.7mmol)，室温下反应1h。反应完成后，加入150mL水，用二氯甲烷(100mL×3)萃取，有机相经无水硫酸镁干燥，抽滤，蒸干滤液，柱层析分离得黄色固体2.87g，收率71.5％。1H NMR(600MHz,Chloroform-d)δ10.24(s,1H),9.18(d,J＝2.0Hz,1H),8.79(s,1H),8.50(d,J＝2.1Hz,1H),8.45(d,J＝8.2Hz,1H),7.39(d,J＝5.3Hz,4H),7.34–7.30(m,2H),7.10(d,J＝7.6Hz,1H),4.91(t,J＝8.0Hz,2H),3.24(t,J＝8.0Hz,2H).ESI-MS m/z:353.1[M+H]+。
步骤9：2-(((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙-1-醇
室温下，将4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-甲醛(80mg,0.22mmol)溶于二氯甲烷(2mL)和甲醇(2mL)的混合溶液中，加入乙醇胺(42mg,0.68mmol)和冰醋酸(14mg,0.22mmol)，室温反应30min，随后加入NaBH3CN(42mg,0.68mmol)，室温反应2h。反应完成后，浓缩反应液，加入15mL水，用二氯甲烷(15mL×3)萃取，有机层经无水硫酸镁干燥后，抽滤，蒸干滤液并用柱层析纯化(MeOH/DCM，1/30-1/10)制得黄色固体76mg，收率84.2％。1H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.72(s,1H),8.43(d,J＝8.2Hz,1H),8.10(s,1H),7.55–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.37–7.33(m,1H),7.11(d,J＝7.6Hz,1H),4.89(t,J＝8.0Hz,2H),4.54(s,1H),3.97(s,2H),3.51(d,J＝7.0Hz,2H),3.27(t,J＝8.1Hz,2H),2.63(s,2H).13C NMR(151MHz,DMSO-d6)δ157.96,154.78,149.08,147.81,144.86,141.42,140.35,138.33,133.76,132.27,131.06,129.01(2C),128.65(2C),127.77,127.61,124.14,117.80,60.86,54.59,51.46,50.31,29.04.ESI-MSm/z:398.2[M+H]+。
按照实施例1中步骤9的合成方法以4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-甲醛为原料与相应的小分子胺经还原胺化制得实施例2-25中的目标化合物。
实施例2：2-甲基-2-(((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)丙-1-醇(化合物I-2)
1H NMR(600MHz,DMSO-d6)δ8.87(d,J＝2.1Hz,1H),8.72(s,1H),8.42(d,J＝8.2Hz,1H),8.13(d,J＝2.1Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.37–7.34(m,1H),7.11(d,J＝7.6Hz,1H),4.88(t,J＝8.1Hz,2H),3.94(s,2H),3.33(s,2H),3.27(t,J＝8.2Hz,2H),1.06(s,6H).13C NMR(151MHz,DMSO-d6)δ157.99,154.74,149.30,147.85,144.88,142.78,140.35,138.34,133.55,132.08,131.06,129.02(2C),128.66(2C),127.77,127.61,124.11,117.76,70.25,68.64,54.61,43.48,29.05,24.26(2C).ESI-MS m/z:426.2[M+H]+。
实施例3：N-2-(((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙基)乙酰胺(化合物I-3)
1H NMR(600MHz,DMSO-d6)δ8.86(s,1H),8.72(s,1H),8.43(d,J＝8.2Hz,1H),8.10(s,1H),7.83(t,J＝5.8Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.43–7.38(m,1H),7.38–7.33(m,1H),7.12(d,J＝7.6Hz,1H),4.89(t,J＝8.1Hz,2H),3.95(s,2H),3.27(t,J＝8.1Hz,2H),3.17(q,J＝6.3Hz,2H),2.60(t,J＝6.5Hz,2H),1.80(s,3H).13C NMR(151MHz,DMSO-d6)δ169.64,157.99,154.80,149.11,147.82,144.86,141.36,140.34,138.34,133.79,132.29,131.07,129.01(2C),128.66(2C),127.77,127.61,124.15,117.80,54.61,50.12,48.57,39.15,29.05,23.13.ESI-MS m/z:439.2[M+H]+。
实施例4：2-甲氧基N-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)乙-1-胺(化合物I-4)
1H NMR(600MHz,DMSO-d6)δ8.85(d,J＝2.1Hz,1H),8.72(s,1H),8.42(s,1H),8.09(d,J＝2.1Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.37–7.34(m,1H),7.11(d,J＝7.5Hz,1H),4.89(t,J＝8.1Hz,2H),3.97(s,2H),3.43(t,J＝5.6Hz,2H),3.28–3.24(m,5H),2.70(t,J＝5.7Hz,2H).13C NMR(151MHz,DMSO-d6)δ158.06,154.85,149.16,147.83,144.88,141.24,140.35,138.38,133.90,132.35,131.13,129.04(2C),128.68(2C),127.80,127.64,124.18,117.80,72.05,58.51,54.66,50.26,48.26,29.08.ESI-MS m/z:412.1[M+H]+。
实施例5：N-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)四氢-2H-吡喃-4-胺(化合物I-5)
1H NMR(600MHz,DMSO-d6)δ8.88(d,J＝2.1Hz,1H),8.72(s,1H),8.43(d,J＝8.1Hz,1H),8.12(d,J＝2.1Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.36(t,J＝7.9Hz,1H),7.12(d,J＝7.6Hz,1H),4.89(t,J＝8.1Hz,2H),3.99(s,2H),3.86–3.81(m,2H),3.30–3.24(m,4H),2.67–2.60(m,1H),1.85–1.77(m,2H),1.36–1.26(m,2H).13C NMR(151MHz,DMSO-d6)δ157.53,154.29,148.66,147.30,144.34,141.38,139.79,137.83,133.23,131.72,130.59,128.49(2C),128.12(2C),127.25,127.08,123.62,117.23,65.67(2C),59.65,54.11,52.48,46.37,32.97,28.52.ESI-MS m/z:438.2[M+H]+。
实施例6：(2-(((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙基)氮烷磺酰胺(化合物I-6)
1H NMR(600MHz,DMSO-d6)δ8.85(s,1H),8.71(s,1H),8.42(d,J＝8.2Hz,1H),8.10(s,1H),7.54–7.46(m,4H),7.42–7.37(m,1H),7.37–7.32(m,1H),7.11(d,J＝7.6Hz,1H),6.58(s,2H),6.49(t,J＝6.2Hz,1H),4.87(t,J＝8.0Hz,2H),3.95(s,2H),3.25(t,J＝8.2Hz,2H),3.05(q,J＝6.4Hz,2H),2.71(t,J＝6.4Hz,2H).13C NMR(151MHz,DMSO-d6)δ158.04,154.84,149.15,147.84,144.88,141.26,140.35,138.37,133.86,132.32,131.12,129.04(2C),128.68(2C),127.81,127.64,124.18,117.81,54.64,50.01,48.38,42.83,29.07.ESI-MS m/z:476.2[M+H]+。
实施例7：N-(2-(((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙基)甲磺酰胺(化合物I-7)
ESI-MS m/z:475.2[M+H]+。
实施例8：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-L-丙氨酸(化合物I-8)
ESI-MS m/z:425.2[M+H]+。
实施例9：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-D-丙氨酸(化合物I-9)
ESI-MS m/z:442.2[M+H]+。
实施例10：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-L-别苏氨酸(化合物I-10)
ESI-MS m/z:456.2[M+H]+。
实施例11：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-L-丝氨酸(化合物I-12)
ESI-MS m/z:442.2[M+H]+。
实施例12：(R)-2-羟基-3-(((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)丙酸(化合物I-13)
ESI-MS m/z:425.1[M+H]+。
实施例13：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)甘氨酸甲酯(化合物I-14)
1H NMR(600MHz,DMSO-d6)δ8.84(d,J＝2.1Hz,1H),8.72(s,1H),8.45–8.40(m,1H),8.08(dd,J＝2.1,1.1Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.38–7.34(m,1H),7.12(dd,J＝7.6,1.0Hz,1H),4.88(t,J＝8.1Hz,2H),3.98(s,2H),3.64(s,3H),3.42(s,2H),3.27(t,J＝8.1Hz,2H).ESI-MS m/z:426.1[M+H]+。
实施例14：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-D-丝氨酸甲酯(化合物I-15)
1H NMR(600MHz,DMSO-d6)δ8.84(d,J＝2.1Hz,1H),8.72(s,1H),8.43(d,J＝7.8Hz,1H),8.11–8.07(m,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.38–7.33(m,1H),7.12(dd,J＝7.6,1.0Hz,1H),4.93–4.85(m,3H),4.06(d,J＝14.9Hz,1H),3.89(d,J＝15.0Hz,1H),3.66–3.62(m,5H),3.35(t,J＝5.5Hz,1H),3.27(t,J＝8.1Hz,2H).ESI-MSm/z:456.2[M+H]+。
实施例15：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)丙氨酸甲酯(化合物I-16)
1H NMR(600MHz,DMSO-d6)δ8.83(d,J＝2.1Hz,1H),8.71(s,1H),8.43(d,J＝8.2Hz,1H),8.09–8.05(m,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.43–7.37(m,1H),7.35(t,J＝7.9Hz,1H),7.11(dd,J＝7.6,1.0Hz,1H),4.88(t,J＝8.1Hz,2H),4.00(d,J＝14.3Hz,1H),3.85(d,J＝14.9Hz,1H),3.64(s,3H),3.37(q,1H),3.26(t,J＝8.1Hz,2H),1.26(d,J＝7.0Hz,3H).ESI-MS m/z:440.2[M+H]+。
实施例16：(S)-1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇(化合物I-17)
1H NMR(600MHz,DMSO-d6)δ8.83(d,J＝2.1Hz,1H),8.72(s,1H),8.44–8.42(m,1H),8.05(d,J＝2.0Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.38–7.34(m,1H),7.12(dd,J＝7.6,1.0Hz,1H),4.89(t,J＝8.1Hz,2H),4.74(d,J＝4.6Hz,1H),4.26–4.19(m,1H),3.86(d,J＝13.9Hz,1H),3.79(d,J＝13.9Hz,1H),3.27(t,J＝8.1Hz,2H),2.76–2.72(m,1H),2.70–2.65(m,1H),2.49–2.46(m,1H),2.42–2.39(m,1H),2.07–1.99(m,1H),1.62–1.54(m,1H).13C NMR(151MHz,DMSO-d6)δ158.02,154.89,149.27,147.78,144.85,140.34,139.62,138.37,134.56,132.53,131.13,129.03(2C),128.67(2C),127.80,127.64,124.21,117.84,69.87,62.96,56.92,54.64,52.89,34.93,29.08.ESI-MSm/z:424.2[M+H]+。
实施例17：(R)-1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-醇(化合物I-18)
1H NMR(600MHz,DMSO-d6)δ8.83(d,J＝2.1Hz,1H),8.72(s,1H),8.43(d,J＝8.1Hz,1H),8.05(d,J＝2.0Hz,1H),7.53–7.51(m,2H),7.50–7.47(m,2H),7.42–7.38(m,1H),7.37–7.34(m,1H),7.11(dd,J＝7.6,1.0Hz,1H),4.89(t,J＝8.1Hz,2H),4.75(d,J＝4.5Hz,1H),4.25–4.20(m,1H),3.85(d,J＝13.9Hz,1H),3.79(d,J＝13.9Hz,1H),3.26(t,J＝8.1Hz,2H),2.75–2.72(m,1H),2.69–2.65(m,1H),2.49–2.45(m,1H),2.42–2.39(m,1H),2.07–1.99(m,1H),1.62–1.55(m,1H).13C NMR(151MHz,DMSO-d6)δ156.75,153.62,148.01,146.51,143.58,139.06,138.36,137.10,133.28,131.26,129.86(2C),127.76(2C),127.40,126.52,126.36,122.94,116.57,68.59,61.69,55.64,53.37,51.62,33.65,27.80.ESI-MSm/z:424.2[M+H]+。
实施例18：(S)-(1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-2-基)甲醇(化合物I-19)
1H NMR(600MHz,DMSO-d6)δ8.83(d,J＝2.1Hz,1H),8.72(s,1H),8.43(d,J＝8.1Hz,1H),8.04(d,J＝2.1Hz,1H),7.53–7.51(m,2H),7.50–7.47(m,2H),7.42–7.38(m,1H),7.38–7.34(m,1H),7.12(d,J＝7.5Hz,1H),4.89(t,J＝8.1Hz,2H),4.57(s,1H),3.83(d,J＝13.8Hz,1H),3.79(d,J＝13.8Hz,1H),3.32–3.28(m,2H),3.26(t,J＝8.0Hz,2H),2.62–2.52(m,3H),2.39–2.33(m,1H),2.29–2.19(m,1H),1.89–1.79(m,1H),1.46–1.36(m,1H).13C NMR(151MHz,DMSO-d6)δ156.96,153.83,148.19,146.73,143.80,139.28,138.78,137.31,133.43,131.46,130.07,127.98(2C),127.61(2C),126.74,126.58,123.15,116.79,69.19,63.95,56.25,55.82,53.58,52.83,28.01,26.34.ESI-MS m/z:438.3[M+H]+。
实施例19：(R)-(1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-2-基)甲醇(化合物I-20)
1H NMR(600MHz,DMSO-d6)δ8.83(d,J＝2.1Hz,1H),8.72(s,1H),8.44(d,J＝8.1Hz,1H),8.04(d,J＝2.1Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.38–7.34(m,1H),7.12(dd,J＝7.6,1.0Hz,1H),4.90(t,J＝8.2Hz,2H),4.56(s,1H),3.83(d,J＝13.8Hz,1H),3.78(d,J＝13.8Hz,1H),3.32–3.24(m,4H),2.59–2.51(m,3H),2.37–2.33(m,1H),2.27–2.19(m,1H),1.87–1.80(m,1H),1.44–1.37(m,1H).13C NMR(151MHz,DMSO-d6)δ157.97,154.87,149.21,147.78,144.85,140.35,139.79,138.36,134.47,132.50,131.10,129.03(2C),128.67(2C),127.79,127.63,124.20,117.85,70.26,65.02,57.32,56.89,54.61,53.90,29.05,27.41.ESI-MS m/z:438.2[M+H]+。
实施例20：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-D-脯氨酸(化合物I-21)
1H NMR(600MHz,DMSO-d6)δ8.87(d,J＝2.0Hz,1H),8.71(s,1H),8.42(d,J＝8.1Hz,1H),8.08(d,J＝2.1Hz,1H),7.53–7.50(m,2H),7.50–7.47(m,2H),7.42–7.38(m,1H),7.37–7.33(m,1H),7.11(d,J＝7.5Hz,1H),4.88(t,J＝8.0Hz,2H),4.19(d,J＝13.9Hz,1H),3.81(d,J＝14.1Hz,1H),3.33–3.28(m,1H),3.25(t,J＝8.1Hz,2H),3.00–2.93(m,1H),2.49–2.43(m,1H),2.15–2.06(m,1H),1.92–1.82(m,1H),1.80–1.73(m,2H).13C NMR(151MHz,DMSO-d6)δ174.77,158.00,154.88,149.47,147.70,144.84,140.34,139.16,138.36,134.76,132.58,131.12,129.02(2C),128.67(2C),127.79,127.63,124.20,117.83,65.54,55.12,54.63,53.26,29.33,29.06,23.40.ESI-MS m/z:452.2[M+H]+。
实施例21：((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-L-脯氨酸(化合物I-22)
1H NMR(600MHz,DMSO-d6)δ8.87(s,1H),8.71(s,1H),8.42(d,J＝8.2Hz,1H),8.08(s,1H),7.54–7.46(m,4H),7.43–7.37(m,1H),7.35(t,J＝7.9Hz,1H),7.11(d,J＝7.6Hz,1H),4.87(t,J＝8.2Hz,2H),4.19(d,J＝13.9Hz,1H),3.83(d,J＝14.0Hz,1H),3.33(d,J＝7.7Hz,1H),3.25(t,J＝8.2Hz,2H),2.97(s,1H),2.49–2.44(m,1H),2.16–2.07(m,1H),1.92–1.83(m,1H),1.81–1.70(m,2H).13C NMR(151MHz,DMSO-d6)δ174.79,157.98,154.86,149.47,147.68,144.83,140.33,139.17,138.35,134.75,132.57,131.11,129.02(2C),128.66(2C),127.78,127.62,124.19,117.82,65.56,55.12,54.63,53.25,29.33,29.06,23.40.ESI-MS m/z:452.2[M+H]+。
实施例22：(S)-1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-羧酸(化合物I-23)
1H NMR(600MHz,DMSO-d6)δ8.82(d,J＝2.1Hz,1H),8.71(s,1H),8.43(d,J＝8.1Hz,1H),8.05(d,J＝2.1Hz,1H),7.53–7.47(m,4H),7.42–7.38(m,1H),7.37–7.33(m,1H),7.11(dd,J＝7.6,1.0Hz,1H),4.88(t,J＝8.1Hz,2H),3.86(d,J＝13.9Hz,1H),3.80(d,J＝13.9Hz,1H),3.25(t,J＝8.2Hz,2H),3.02–2.94(m,1H),2.77(t,J＝8.7Hz,1H),2.72(dd,J＝9.2,6.3Hz,1H),2.58(t,J＝6.9Hz,2H),2.04–1.95(m,2H).13C NMR(151MHz,DMSO-d6)δ175.21,156.96,153.84,148.14,146.71,143.79,139.28,138.52,137.30,133.45,131.49,130.07,127.97(2C),127.61(2C),126.74,126.57,123.15,116.78,55.56,55.30,53.57,52.72,40.96,28.00,26.60.ESI-MS m/z:452.2[M+H]+。
实施例23：(R)-1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)吡咯烷-3-羧酸(化合物I-24)
1H NMR(600MHz,DMSO-d6)δ8.82(d,J＝2.1Hz,1H),8.71(s,1H),8.43(d,J＝8.2Hz,1H),8.05–8.03(m,1H),7.53–7.50(m,2H),7.50–7.47(m,2H),7.41–7.38(m,1H),7.37–7.34(m,1H),7.11(d,J＝7.6Hz,1H),4.89(t,J＝8.2Hz,2H),3.83(d,J＝13.8Hz,1H),3.78(d,J＝13.9Hz,1H),3.26(t,J＝8.0Hz,2H),2.84–2.78(m,1H),2.75–2.71(m,1H),2.67(t,J＝7.8Hz,1H),2.64–2.51(m,2H),2.03–1.95(m,1H),1.94–1.87(m,1H).13C NMR(151MHz,DMSO-d6)δ176.21,158.07,154.93,149.27,147.78,144.86,140.34,139.52,138.39,134.58,132.58,131.17,129.06(2C),128.68(2C),127.82,127.66,124.24,117.85,56.60,56.33,54.67,53.78,42.02,29.08,27.67.ESI-MS m/z:452.2[M+H]+。
实施例24：(R)-1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)哌啶-2-羧酸(化合物I-26)
1H NMR(600MHz,DMSO-d6)δ8.87(d,J＝2.1Hz,1H),8.72(s,1H),8.44(d,J＝8.2Hz,1H),8.06(d,J＝2.1Hz,1H),7.54–7.46(m,4H),7.42–7.38(m,1H),7.38–7.34(m,1H),7.12(d,J＝7.6Hz,1H),4.89(t,J＝8.1Hz,2H),4.01(d,J＝14.6Hz,1H),3.72(d,J＝14.5Hz,1H),3.29–3.23(m,3H),2.91–2.86(m,1H),2.29–2.24(m,1H),1.87–1.73(m,2H),1.56–1.45(m,3H),1.44–1.37(m,1H).13C NMR(151MHz,DMSO-d6)δ174.93,157.99,154.84,149.41,147.70,144.85,140.35,139.48,138.36,134.63,132.57,131.10,129.02(2C),128.67(2C),127.78,127.63,124.18,117.83,64.01,57.04,54.63,49.57,29.47,29.06,25.38,22.33.ESI-MS m/z:466.2[M+H]+。
实施例25：(S)-1-((4-(4-苯基吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)哌啶-2-羧酸(化合物I-27)
1H NMR(600MHz,DMSO-d6)δ8.87(d,J＝2.1Hz,1H),8.72(s,1H),8.44(d,J＝8.2Hz,1H),8.07(s,1H),7.55–7.51(m,2H),7.51–7.46(m,2H),7.42–7.38(m,1H),7.38–7.34(m,1H),7.12(d,J＝7.6Hz,1H),4.90(t,J＝8.1Hz,2H),4.01(d,J＝14.6Hz,1H),3.72(d,J＝14.5Hz,1H),3.30–3.23(m,3H),2.92–2.86(m,1H),2.30–2.23(m,1H),1.86–1.74(m,2H),1.54–1.39(m,4H).13C NMR(151MHz,DMSO-d6)δ174.93,157.98,154.84,149.40,147.69,144.85,140.35,139.47,138.36,134.64,132.57,131.09,129.02(2C),128.66(2C),127.78,127.63,124.18,117.83,64.02,57.03,54.62,49.57,29.47,29.06,25.38,22.33.ESI-MS m/z:466.2[M+H]+。
实施例26：2-(((4-(4-苯基吲哚啉-1-基)喹唑啉-7-基)甲基)氨基)乙-1-醇(化合物I-28)
步骤1：7-溴-3,4-二氢喹唑啉-4-酮
将2-氨基-4-溴苯甲酸(5g,23.2mmol)、甲酸(1.07g,23.2mmol)依次加入到15mL甲酰胺中，145℃下反应8h。反应完成后加反应液冷却至室温，有大量棕褐色固体析出，抽滤，滤饼用水洗涤三次，干燥滤饼得棕褐色固体4.51g，收率86.5％。ESI-MS m/z:225.0[M+H]+。
步骤2：7-溴-4-氯喹唑啉
将7-溴-3,4-二氢喹唑啉-4-酮(4g,17.9mmol)、DIPEA(6.92g,53.6mmol)溶于40mL的干燥甲苯中，冰浴下缓慢滴加POCl3(4.07g,26.8mml)，加毕，90℃反应1h。反应完成后，将反应液倒入120mL水中，乙酸乙酯(100mL×3)萃取，用无水硫酸钠干燥有机相，抽滤，蒸干滤液，柱层析分离纯化得白色固体3.85g，收率89.1％。1H NMR(600MHz,DMSO-d6)δ9.14(s,1H),8.38(d,J＝1.9Hz,1H),8.22(d,J＝8.9Hz,1H),8.05(dd,J＝8.9,1.9Hz,1H).ESI-MS m/z:242.9[M+H]+。
步骤3：4-(4-苯基吲哚啉-1-基)-喹唑啉-7-甲醛
以4-苯基吲哚啉与7-溴-4-氯喹唑啉作为起始原料，按照实施例1中步骤6-8相同的合成方法制得该化合物，为黄色固体。1H NMR(600MHz,DMSO-d6)δ10.26(s,1H),8.85(s,1H),8.46(d,J＝1.7Hz,1H),8.31(d,J＝8.7Hz,1H),7.94(dd,J＝8.7,1.7Hz,1H),7.54–7.48(m,5H),7.43–7.39(m,1H),7.30–7.26(m,1H),7.11(d,J＝7.6Hz,1H),4.47(t,J＝7.8Hz,2H),3.25(t,J＝7.7Hz,2H).ESI-MS m/z:352.1[M+H]+。
步骤4：2-(((4-(4-苯基吲哚啉-1-基)喹唑啉-7-基)甲基)氨基)乙-1-醇
按照实施例1中步骤9的合成方法，以4-(4-苯基吲哚啉-1-基)-喹唑啉-7-甲醛为原料与乙醇胺反应，再经氰基硼氢化钠还原制得该化合物。1H NMR(600MHz,DMSO-d6)δ8.74(s,1H),8.09(d,J＝8.6Hz,1H),7.87(d,J＝1.8Hz,1H),7.57(dd,J＝8.7,1.8Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.35(d,J＝8.0Hz,1H),7.27–7.21(m,1H),7.06(d,J＝7.6Hz,1H),4.40(t,J＝7.8Hz,2H),3.99(s,2H),3.55(t,J＝5.8Hz,2H),3.23(t,J＝7.8Hz,2H),2.69(t,J＝5.7Hz,2H).13C NMR(151MHz,DMSO-d6)δ160.10,154.51,152.27,146.46,145.65,140.17,138.58,131.07,129.07(2C),128.63(2C),127.87,127.48,126.76,126.58,125.71,123.21,115.87,114.86,60.47,54.57,52.64,51.34,29.15.ESI-MS m/z:397.2[M+H]+。
按照实施例1中步骤9的合成方法以4-(4-苯基吲哚啉-1-基)-喹唑啉-7-甲醛为原料与相应的小分子胺经还原胺化制得实施例27和28中的化合物。
实施例27：N-(2-(((4-(4-苯基吲哚啉-1-基)喹唑啉-7-基)甲基)氨基)乙基)乙酰胺(化合物I-30)
1H NMR(600MHz,DMSO-d6)δ8.75(s,1H),8.10(d,J＝8.6Hz,1H),7.91–7.86(m,2H),7.57(dd,J＝8.7,1.8Hz,1H),7.54–7.52(m,2H),7.51–7.48(m,2H),7.43–7.38(m,1H),7.38–7.34(m,1H),7.27–7.21(m,1H),7.06(dd,J＝7.6,1.0Hz,1H),4.41(t,J＝7.9Hz,2H),3.99(s,2H),3.26–3.18(m,4H),2.67(t,J＝6.5Hz,2H),1.82(s,3H).13C NMR(151MHz,DMSO-d6)δ169.81,160.10,154.54,152.26,146.12,145.64,140.16,138.59,131.08,129.07(2C),128.63(2C),127.88,127.48,126.85,126.59,125.75,123.23,115.91,114.86,54.58,52.39,48.49,38.75,29.16,23.14.ESI-MS m/z:438.2[M+H]+。
实施例28：N-((4-(4-苯基吲哚啉-1-基)喹唑啉-7-基)甲基)四氢-2H-吡喃-4-胺(化合物I-31)
1H NMR(600MHz,DMSO-d6)δ8.73(s,1H),8.07(d,J＝8.7Hz,1H),7.86(d,J＝1.7Hz,1H),7.57(dd,J＝8.7,1.8Hz,1H),7.54–7.51(m,2H),7.51–7.47(m,2H),7.42–7.38(m,1H),7.34(d,J＝8.0Hz,1H),7.25–7.22(m,1H),7.05(dd,J＝7.7,0.9Hz,1H),4.40(t,J＝7.8Hz,2H),3.96(s,2H),3.87–3.81(m,2H),3.29–3.24(m,2H),3.23(t,J＝7.8Hz,2H),2.69–2.61(m,1H),1.84–1.79(m,2H),1.36–1.28(m,2H).13C NMR(151MHz,DMSO-d6)δ160.08,154.44,152.28,147.86,145.68,140.17,138.56,131.04,129.05(2C),128.62(2C),127.85,127.46,126.53,126.37,125.56,123.16,115.72,114.81,66.30(2C),55.39,54.56,53.18,49.61,33.64,29.15.ESI-MS m/z:437.3[M+H]+。
实施例29：2-(((8-4-苯基吲哚啉-1-基)-1,7-萘啶-3-基)甲基)氨基)乙-1-醇(化合物I-32)
步骤1：5-溴--3-甲基吡啶-2-甲酰胺
冰浴下，将5-溴-3-甲基吡啶-2-甲腈(10g,51.0mmol)缓慢加入到50mL浓硫酸中，加毕，40℃反应4h。反应完成后，将反应液缓慢滴加到冰水中，用10M NaOH调pH至8-9，有大量白色固体析出，用二氯甲烷萃取三次，合并有机相，有机相用饱和食盐水洗涤一次，后用无水硫酸钠干燥，抽滤，蒸干滤液得白色固体10.72g，收率98.2％。1H NMR(600MHz,DMSO-d6)δ8.62(d,J＝2.2Hz,1H),8.14(d,J＝2.2Hz,1H),4.33(q,J＝7.1Hz,2H),2.45(s,3H).ESI-MS m/z:215.0[M+H]+。
步骤2：5-溴-N-((二甲氨基)亚甲基)-3-甲基吡啶酰胺
将5-溴-3-甲基吡啶-2-甲酰胺(10g,46.7mmol)加入到50mL DMF-DMA中，50℃反应6h。反应完成后，浓缩反应液，残留物无需纯化，直接用于下一步。ESI-MS m/z:270.0[M+H]+。
步骤3：3-溴-1,7-萘啶-8(7H)-酮
将5-溴-N-((二甲氨基)亚甲基)-3-甲基吡啶酰胺(12.6g,46.7mmol)、叔丁醇钾(8.5g,70.1mmol)依次加入到100mL的四氢呋喃中，N2保护下回流反应3h。反应完成后，将反应液冷却至室温，将反应液倒入水中，用2M HCl溶液调节pH至2-3，有大量固体析出，抽滤，干燥，得粉色固体7.54g，两步总收率为69.2％。ESI-MS m/z:225.1[M+H]+。
步骤4：3-溴-8-氯-1,7-萘啶
以3-溴-1,7-萘啶-8(7H)-酮为起始原料按照实施例1中步骤5的合成方法来制备该化合物。1H NMR(600MHz,DMSO-d6)δ9.21(d,J＝2.3Hz,1H),8.93(d,J＝2.3Hz,1H),8.47(d,J＝5.6Hz,1H),7.93(d,J＝5.5Hz,1H).ESI-MS m/z:242.9[M+H]+。
步骤5：8-(4-苯基吲哚啉-1-基)-1,7-萘啶-3-甲醛
以4-苯基吲哚啉与3-溴-8-氯-1,7-萘啶作为起始原料，按照实施例1中步骤6-8相同的合成方法制得该化合物，为红色固体。1H NMR(600MHz,DMSO-d6)δ10.28(s,1H),9.23(d,J＝2.1Hz,1H),8.89(d,J＝2.1Hz,1H),8.32(d,J＝5.4Hz,1H),7.60–7.55(m,2H),7.52(d,J＝7.6Hz,2H),7.50–7.46(m,2H),7.41–7.35(m,1H),7.23–7.16(m,1H),6.96(d,J＝7.6Hz,1H),4.60(t,J＝8.1Hz,2H),3.22(t,J＝8.2Hz,2H).ESI-MS m/z:352.1[M+H]+。
步骤6：2-(((8-4-苯基吲哚啉-1-基)-1,7-萘啶-3-基)甲基)氨基)乙-1-醇
按照实施例1中步骤9的合成方法，以8-(4-苯基吲哚啉-1-基)-1,7-萘啶-3-甲醛为原料与乙醇胺反应，再经氰基硼氢化钠还原制得该化合物。1H NMR(600MHz,DMSO-d6)δ8.85(d,J＝2.2Hz,1H),8.21–8.18(m,2H),7.53–7.50(m,3H),7.49–7.46(m,2H),7.40–7.36(m,2H),7.19–7.16(m,1H),6.92(d,J＝7.6Hz,1H),4.57(t,J＝8.2Hz,2H),3.95(s,2H),3.53(t,J＝5.8Hz,2H),3.20(t,J＝8.2Hz,2H),2.65(t,J＝5.8Hz,2H).13C NMR(151MHz,DMSO-d6)δ154.86,149.96,147.13,141.89,140.77,138.46,138.08,135.29,133.64,133.17,129.95,128.97(2C),128.63(2C),127.58,127.25,121.54,114.34,114.28,60.84,54.45,51.58,50.66,28.99.ESI-MS m/z:397.2[M+H]+。
按照实施例1中步骤9的合成方法以8-(4-苯基吲哚啉-1-基)-1,7-萘啶-3-甲醛为原料与相应的小分子胺类化合物经还原胺化制得实施例30-34中的化合物。
实施例30：2-甲基-2-(((8-4-苯基吲哚啉-1-基)-1,7-萘啶-3-基)甲基)氨基)丙-1-醇(化合物I-33)
1H NMR(600MHz,DMSO-d6)δ8.85(d,J＝2.2Hz,1H),8.22(d,J＝2.1Hz,1H),8.18(d,J＝5.5Hz,1H),7.51(t,J＝7.8Hz,3H),7.50–7.45(m,2H),7.39(d,J＝5.4Hz,2H),7.19–7.15(m,1H),6.92(d,J＝7.5Hz,1H),4.57(t,J＝8.2Hz,2H),3.91(s,2H),3.31(s,2H),3.20(t,J＝8.2Hz,2H),1.06(s,6H).13C NMR(151MHz,DMSO-d6)δ154.85,150.18,147.15,141.86,140.77,139.52,138.08,135.18,133.67,133.00,129.95,128.97(2C),128.63(2C),127.59,127.24,121.51,114.39,114.21,70.26,68.51,54.43,43.70,28.97,24.20(2C).ESI-MS m/z:425.3[M+H]+。
实施例31：N-(2-(((8-4-苯基吲哚啉-1-基)-1,7-萘啶-3-基)甲基)氨基)乙基)乙酰胺(化合物I-34)
1H NMR(600MHz,DMSO-d6)δ8.87(s,1H),8.20(d,J＝6.4Hz,2H),7.83(t,J＝5.7Hz,1H),7.56–7.47(m,5H),7.42–7.37(m,2H),7.21–7.16(m,1H),6.93(d,J＝7.6Hz,1H),4.59(t,J＝8.2Hz,2H),3.94(s,2H),3.25–3.16(m,4H),2.62(t,J＝6.6Hz,2H),1.81(s,3H).13CNMR(151MHz,DMSO-d6)δ169.64,154.86,149.99,147.11,141.91,140.76,138.30,138.08,135.28,133.61,133.23,129.95,128.96(2C),128.62(2C),127.58,127.24,121.55,114.32,114.26,54.46,50.41,48.63,39.11,28.99,23.14.ESI-MS m/z:438.2[M+H]+。
实施例32：N-((8-(4-苯基吲哚啉-1-基)-1,7-萘啶-3-基)甲基)四氢-2H-吡喃-4-胺(化合物I-35)
1H NMR(600MHz,DMSO-d6)δ8.87(d,J＝2.2Hz,1H),8.22(s,1H),8.19(d,J＝5.5Hz,1H),7.54–7.46(m,5H),7.41–7.37(m,2H),7.20–7.15(m,1H),6.92(d,J＝7.6Hz,1H),4.58(t,J＝8.2Hz,2H),3.98(s,2H),3.84(dt,J＝11.7,3.6Hz,2H),3.31–3.25(m,2H),3.21(t,J＝8.2Hz,2H),2.72–2.63(m,1H),1.86–1.81(m,2H),1.38–1.28(m,2H).13C NMR(151MHz,DMSO-d6)δ154.88,150.03,147.14,141.92,140.77,138.10,135.26,133.64,133.20,129.97,128.99(2C),128.64(2C),127.61,127.26,121.56,114.38,114.25,66.28(2C),65.40,54.47,53.33,47.29,33.48,28.99,15.64.ESI-MS m/z:437.3[M+H]+。
实施例33：(S)-1-((8-4-苯基吲哚啉-1-基)-1,7-萘啶-3-基)甲基)吡咯烷-3-羧酸(化合物I-40)
1H NMR(600MHz,DMSO-d6)δ8.81(d,J＝2.1Hz,1H),8.20–8.17(m,2H),7.57–7.50(m,3H),7.50–7.46(m,2H),7.40–7.36(m,2H),7.21–7.15(m,1H),6.92(d,J＝7.6Hz,1H),4.58(t,J＝8.5Hz,2H),3.85–3.76(m,2H),3.20(t,J＝8.2Hz,2H),3.02–2.94(m,1H),2.79(t,J＝8.8Hz,1H),2.70(dd,J＝9.2,6.3Hz,1H),2.63–2.53(m,2H),2.06–1.97(m,2H).13CNMR(151MHz,DMSO-d6)δ176.28,154.85,150.01,147.07,141.95,140.77,138.09,136.57,135.42,133.97,133.63,129.97,128.96(2C),128.62(2C),127.58,127.26,121.61,114.37,114.29,56.75,56.70,54.48,53.80,42.01,29.00,27.70.ESI-MS m/z:451.2[M+H]+。
实施例34：(R)-1-((8-4-苯基吲哚啉-1-基)-1,7-萘啶-3-基)甲基)吡咯烷-3-羧酸(化合物I-41)
1H NMR(600MHz,DMSO-d6)δ8.81(d,J＝2.0Hz,1H),8.20–8.17(m,2H),7.55(d,J＝8.1Hz,1H),7.53–7.50(m,2H),7.49–7.46(m,2H),7.40–7.36(m,2H),7.20–7.16(m,1H),6.92(d,J＝7.6Hz,1H),4.60–4.56(m,2H),3.84–3.77(m,2H),3.20(t,J＝8.3Hz,2H),3.01–2.94(m,1H),2.79(t,J＝8.8Hz,1H),2.72–2.68(m,1H),2.62–2.54(m,2H),2.03–1.97(m,2H).13C NMR(151MHz,DMSO-d6)δ176.27,154.85,150.00,147.07,141.95,140.77,138.09,136.57,135.42,133.97,133.63,129.97,128.96(2C),128.62(2C),127.58,127.26,121.61,114.37,114.29,56.75,56.70,54.48,53.80,42.01,29.00,27.70.ESI-MS m/z:451.2[M+H]+。
实施例35：2-(((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙-1-醇(化合物I-42)
步骤1：1,4-苯并二噁烷-6-硼酸频那醇酯
室温下，将6-溴-苯并二噁烷(10g,46.7mmol)、联硼酸频哪醇酯(14.3g,56.1mmol)、Pd(dppf)Cl2·CH2Cl2(1.15g,1.4mmol)、醋酸钾(11.5g,116.8mmol)依次加入到无水的1,4-二氧六环中，在N2保护下90℃反应3h。反应完成后，将反应液冷却至室温，浓缩反应液，加入200mL乙酸乙酯，垫硅藻土抽滤，滤饼用乙酸乙酯洗涤，浓缩滤液并通过柱层析纯化，制得白色固体11.9g，收率97.4％。
步骤2：4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉
类似实施例1中4-苯基吲哚啉的合成方法，以1,4-苯并二噁烷-6-硼酸频那醇酯与4-溴吲哚为原料经Suzuki-Miyaura偶联反应与Gribble吲哚还原反应制得该中间体，两步总收率74.7％。ESI-MS m/z:254.2[M+H]+。
步骤3：4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-甲醛
以4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉与7-溴-4-氯吡啶并[3,2-d]嘧啶作为起始原料，按照实施例1中步骤6-8相同的合成方法制得该化合物，为黄色固体。1H NMR(600MHz,Chloroform-d)δ10.23(s,1H),9.17(d,J＝2.0Hz,1H),8.78(s,1H),8.48(d,J＝2.1Hz,1H),8.40(d,J＝8.2Hz,1H),7.29(t,J＝7.9Hz,1H),7.06(d,J＝7.6Hz,1H),6.90(d,J＝1.8Hz,1H),6.89–6.84(m,2H),4.89(t,J＝8.0Hz,2H),4.25(s,4H),3.24(t,J＝8.0Hz,2H).ESI-MS m/z:411.1[M+H]+。
步骤4：2-(((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙-1-醇
按照实施例1中步骤9的合成方法，以4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-甲醛为原料与乙醇胺反应，再经氰基硼氢化钠还原制得该目标化合物。1H NMR(600MHz,DMSO-d6)δ8.86(d,J＝2.1Hz,1H),8.71(s,1H),8.38(d,J＝8.1Hz,1H),8.11(d,J＝2.1Hz,1H),7.34–7.28(m,1H),7.06(d,J＝7.6Hz,1H),7.00(d,J＝2.0Hz,1H),6.98–6.94(m,2H),4.87(t,J＝8.1Hz,2H),4.58(s,1H),4.29(s,4H),3.99(s,2H),3.52(t,J＝5.8Hz,2H),3.25(t,J＝8.1Hz,2H),2.65(t,J＝5.8Hz,2H).13C NMR(151MHz,DMSO-d6)δ157.95,154.81,149.09,147.78,144.79,143.73,143.32,140.94,137.82,133.95,133.52,132.35,130.91,127.50,123.98,121.63,117.56,117.46,117.20,64.61,64.58,60.65,54.63,51.33,50.16,29.13.ESI-MS m/z:456.2[M+H]+。
按照实施例1中步骤9的合成方法以4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-甲醛为原料与相应的小分子胺经还原胺化制得实施例36-41中的化合物。
实施例36：2-(((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)-2-甲基丙-1-醇(化合物I-43)
1H NMR(600MHz,DMSO-d6)δ8.86(d,J＝2.1Hz,1H),8.70(s,1H),8.37(d,J＝8.1Hz,1H),8.10(d,J＝2.1Hz,1H),7.33–7.28(m,1H),7.05(dd,J＝7.6,1.0Hz,1H),6.99(d,J＝1.9Hz,1H),6.98–6.94(m,2H),4.86(t,J＝8.1Hz,2H),4.64(s,1H),4.29(s,4H),3.91(s,2H),3.29(d,J＝4.3Hz,2H),3.25(t,J＝8.1Hz,2H),1.04(s,6H).13C NMR(151MHz,DMSO-d6)δ156.87,153.96,148.55,146.36,143.64,142.67,142.28,136.81,132.41,131.76,129.92,129.03,126.48,123.08,120.57,116.51,116.47,116.14,69.18,63.52,53.60,41.49,28.07,21.19.ESI-MS m/z:484.3[M+H]+。
实施例37：N-(2-(((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基)乙基)乙酰胺(化合物I-44)
1H NMR(600MHz,DMSO-d6)δ8.85(d,J＝2.1Hz,1H),8.71(s,1H),8.38(d,J＝8.1Hz,1H),8.10(d,J＝2.1Hz,1H),7.83(t,J＝5.8Hz,1H),7.34–7.28(m,1H),7.06(dd,J＝7.7,1.0Hz,1H),7.00(d,J＝1.9Hz,1H),6.98–6.94(m,2H),4.87(t,J＝8.1Hz,2H),4.29(s,4H),3.95(s,2H),3.25(t,J＝8.1Hz,2H),3.17(q,J＝6.3Hz,2H),2.60(t,J＝6.5Hz,2H),1.80(s,3H).13CNMR(151MHz,DMSO-d6)δ169.66,157.99,154.83,149.12,147.84,144.82,143.75,143.35,141.31,137.85,133.83,133.54,132.32,130.94,127.52,124.00,121.65,117.58,117.47,117.22,64.61,64.59,54.65,50.11,48.56,39.13,29.14,23.13.ESI-MSm/z:497.2[M+H]+。
实施例38：N-((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-2-甲氧基乙-1-胺(化合物I-45)
1H NMR(600MHz,DMSO-d6)δ8.84(d,J＝2.1Hz,1H),8.70(s,1H),8.38(d,J＝8.1Hz,1H),8.08(d,J＝2.1Hz,1H),7.37–7.28(m,1H),7.06(dd,J＝7.6,1.0Hz,1H),7.00(d,J＝2.0Hz,1H),6.98–6.94(m,2H),4.87(t,J＝8.1Hz,2H),4.29(s,4H),3.96(s,2H),3.43(t,J＝5.6Hz,2H),3.27–3.23(m,5H),2.70(t,J＝5.7Hz,2H).13C NMR(151MHz,DMSO-d6)δ156.91,153.74,148.00,146.76,143.75,142.68,142.28,140.26,136.78,132.74,132.48,131.25,129.86,126.45,122.91,120.58,116.50,116.40,116.15,71.07,63.55,63.52,57.44,53.56,49.25,47.24,28.07.＝ESI-MS m/z:470.4[M+H]+。
实施例39：N-((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)四氢-2H-吡喃-4-胺(化合物I-46)
1H NMR(600MHz,DMSO-d6)δ8.86(d,J＝2.1Hz,1H),8.70(s,1H),8.38(d,J＝8.1Hz,1H),8.12–8.09(m,1H),7.33–7.28(m,1H),7.06(dd,J＝7.6,1.0Hz,1H),6.99(d,J＝1.9Hz,1H),6.98–6.94(m,2H),4.87(t,J＝8.1Hz,2H),4.29(s,4H),3.98(s,2H),3.87–3.81(m,2H),3.29–3.23(m,4H),2.67–2.61(m,1H),1.84–1.79(m,2H),1.36–1.27(m,2H).13C NMR(151MHz,DMSO-d6)δ158.02,154.84,149.17,147.84,144.84,143.76,143.35,141.69,137.87,133.82,133.54,132.30,130.96,127.54,124.01,121.66,117.59,117.47,117.22,66.24(2C),64.62,64.59,54.67,53.09,46.92,33.48,29.16.ESI-MS m/z:496.2[M+H]+。
实施例40：((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)-L-脯氨酸(化合物I-53)
1H NMR(600MHz,DMSO-d6)δ8.88(s,1H),8.71(s,1H),8.38(d,J＝8.2Hz,1H),8.09(s,1H),7.34–7.28(m,1H),7.06(d,J＝7.6Hz,1H),7.00(d,J＝1.9Hz,1H),7.00–6.92(m,2H),4.87(t,J＝8.1Hz,2H),4.29(s,4H),4.19(d,J＝13.9Hz,1H),3.84(d,J＝13.9Hz,1H),3.35–3.30(m,1H),3.25(t,J＝8.1Hz,2H),3.01–2.95(m,1H),2.50–2.45(m,1H),2.16–2.07(m,1H),1.91–1.83(m,1H),1.81–1.72(m,2H).13C NMR(151MHz,DMSO-d6)δ174.79,157.95,154.87,149.44,147.69,144.77,143.74,143.34,139.12,137.84,134.76,133.52,132.59,130.94,127.52,124.02,121.64,117.57,117.49,117.21,65.58,64.60,55.12,54.64,53.26,29.33,29.14,23.40.ESI-MS m/z:510.3[M+H]+。
实施例41：(2-(((4-(4-(2,3-二氢-1,4-苯并二噁烷-6-基)-吲哚啉-1-基)吡啶并[3,2-d]嘧啶-7-基)甲基)氨基]乙基)氮烷磺酰胺(化合物I-54)
1H NMR(600MHz,DMSO-d6)δ8.84(d,J＝2.2Hz,1H),8.69(s,1H),8.37(d,J＝8.2Hz,1H),8.08(d,J＝2.2Hz,1H),7.30(t,J＝7.9Hz,1H),7.05(d,J＝7.6Hz,1H),6.99(d,J＝1.8Hz,1H),6.98–6.92(m,2H),6.58(s,2H),6.49(t,J＝6.1Hz,1H),4.85(t,J＝8.2Hz,2H),4.29(s,4H),3.94(s,2H),3.23(t,J＝8.2Hz,2H),3.05(q,J＝6.2Hz,2H),2.71(t,J＝6.4Hz,2H).13CNMR(151MHz,DMSO-d6)δ157.98,154.82,149.09,147.83,144.81,143.74,143.34,141.28,137.84,133.80,133.53,132.31,130.92,127.52,123.99,121.65,117.57,117.47,117.21,64.61,64.58,54.64,50.04,48.40,42.87,29.14.ESI-MS m/z:534.2[M+H]+。
本发明化合物药理活性研究
1.实施例化合物对PD-1/PD-L1相互作用抑制活性评价
采用均相时间分辨荧光(Homogenouse Time-Resolved Fluorescence,HTRF)试验来检测本发明化合物抑制PD-1/PD-L1相互作用的能力。检测试剂盒购买于CisBio公司(CAT#64PD1PEG)，其中包含Anti-Tag1 Eu Cyptate、Anti-Tag2 XL665、Tag1-PD-L1、Tag2-PD-1、Detection Buffer等实验所需试剂。
实验步骤：
(1)首先用DMSO将待测化合物稀释至1mM得到母液，用DMSO以4倍倍比继续稀释化合物母液，6-8个浓度。然后将各个浓度的化合物溶液用Detection buffer稀释20倍，从而得到各个浓度的化合物工作液，每个浓度复孔测试。
(2)将Tag2-PD-1和Tag1-PD-L1储备液用Detection Buffer稀释40倍。
(3)将2μL化合物工作液、4μL Tag2-PD-1和4μL Tag1-PD-L1溶液依次加入到96孔板中，充分混匀，室温孵育15min。
(4)将Anti-Tag1 Eu Cyptate和Anti-Tag2 XL665储备液用Detection buffer稀释50倍，将二者等体积混匀，然后向每个反应孔中加入10μL该混合液，封膜室温孵育1h。
(5)用SpectraMax i3X多功能酶标仪检测荧光信号(320nm激发,665nm、620nm发射)。
化合物抑制PD-1/PD-L1相互作用的活性结果见表1。
表1本发明化合物抑制PD-1/PD-L1相互作用的活性范围或IC50值。范围如下：A＝lnM-100nM；B＝100.01nM-lμM。
HTRF测试结果表明，实施例化合物在生化水平可显著抑制PD-1/PD-L1相互作用。
2.实施例2化合物体内药效评价
体内药效研究方法如下：
(1)LLC/PD-L1细胞的构建
通过慢病毒转染的方式，使用慢病毒包装的过表达PD-L1质粒感染鼠肺癌LLC细胞，感染24h后弃去病毒液，更换新培养液后进行培养传代，并加入嘌呤霉素进行筛选，得到稳定过表达PD-L1的LLC细胞(LLC/PD-L1)。
(2)细胞培养
LLC/PD-L1细胞用含10％FBS的DMEM培养液，37℃，5％ CO2条件下培养并传代至3代后，待细胞长至对数生长期，用0.25％胰酶消化，吹打，制备成单细胞悬液后进行离心收集细胞饼，用PBS调整细胞密度至1×107个/mL，即0.2mL中含有2×106个细胞。
(3)建立C57小鼠皮下异位移植瘤模型
在SPF实验室内，给小鼠腋下剃毛，并用75％酒精进行腋下消毒，皮下接种0.2mL细胞悬液，建立小鼠皮下异位移植瘤模型。在瘤体积长到50-100mm3随机分组，分组后当天通过腹腔注射给予20mg/kg抑制剂，隔2天给一次药，连续给药19天。
(4)考察指标
从给药当天起计算为实验第一天。实验动物给药期间，观察动物生存状态，每次称重、测瘤径并记录实验数据，肿瘤长径a(mm)、短径b(mm)。给药3周，隔两天给一次药。给药周期结束后，剥取肿瘤组织，根据肿瘤体积评价药物对肿瘤生长的抑制作用。
药效学考察：
(a)肿瘤体积(TV)＝1/2×a×b2(a：长径，b：短径)；
(b)相对肿瘤体积(RTV)＝Vt/V0(Vt：每一次测量时的肿瘤体积，V0：给药前测量的肿瘤体积)；(c)抑瘤率(TIR％)＝(1-RTV(给药组)/RTV(空白组))×100％。
试验结果如图1所示，实施例2化合物能显著抑制小鼠肿瘤的生长，治疗结束后，在20mg/kg给药剂量下的抑瘤率为61.86％。
Claims (9)
1.通式I所示的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，
其中，
R1选自苯基或
X、Y各自独立地选自CH或N；
R2、R3各自独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰氨基(C1-C4)烷基、氨基磺酰氨基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基，含有1-3个选自N、O或S原子的4-7元杂环烷基，其中，所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰氨基(C1-C4)烷基、氨基磺酰氨基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基，含有1-3个选自N、O或S原子的4-7元杂环烷基可任选被1-3个R4取代；
或者R2、R3和与它们相连的氮原子一起形成一个3-7元的含氮杂环；所述的含氮杂环含有1-3个选自N、O或S的杂原子；所述的含氮杂环可任选被1-3个R5取代，环上碳原子可被氧代；
R4选自氢、卤素、羟基、羧基、氨基、(C1-C4)烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C1-C4)酰基；
R5选自氢、羟基、羧基、(C1-C4)烷基、(C1-C4)烷氧基、(C1-C4)烷氧甲酰基、羟基(C1-C4)烷基。
2.根据权利要求1所述的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，其特征在于：
R2、R3各自独立地选自氢、(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、氨基磺酰基(C1-C4)烷基、甲磺酰氨基(C1-C4)烷基、氨基磺酰氨基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基，含有1-3个选自N、O或S原子的4-6元杂环烷基；其中，所述(C1-C4)烷基、(C3-C8)环烷基、羟基(C1-C4)烷基、氨基(C1-C4)烷基、氨基甲酰基(C1-C4)烷基、羧基(C1-C4)烷基、(C1-C4)烷氧甲酰基(C1-C4)烷基，含有1-3个选自N、O或S原子的4-6元杂环烷基可任选被1-3个R4取代；
或者R2、R3和与它们相连的氮原子一起形成一个4-6元的含氮杂环；所述的含氮杂环含有1-3个选自N、O的杂原子；所述的含氮杂环可任选被1-3个R5取代，环上碳原子可被氧代；
R4选自氢、羟基、羧基、氨基、(C1-C4)烷基、羟基(C1-C4)烷基、(C1-C4)烷氧基(C1-C4)烷基、(C1-C4)酰基；
R5选自氢、羟基、羧基、(C1-C4)烷基、(C1-C4)烷氧基、羟基(C1-C4)烷基。
3.根据权利要求1所述的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，其特征在于：
4.根据权利要求1所述的含稠合杂环结构的吲哚啉类化合物及其立体异构体以及药学上可接受的盐，其特征在于：所述含稠合杂环结构的吲哚啉类化合物为具有下述I-1～I-57化学结构式的化合物之一：
5.权利要求1所述含稠合杂环结构的吲哚啉类化合物的制备方法，包括下述工艺步骤：
(a)以4-溴-1H-吲哚为原料，与苯硼酸或1,4-苯并二噁烷-6-硼酸频那醇酯通过Suzuki-Miyaura偶联反应制得中间体2；
(b)中间体2在还原剂如氰基硼氢化钠作用下制得中间体3；
(c)以中间体3为原料，在酸催化下与稠合杂环的氯代物反应制得中间体4；
(d)以中间体4为原料，与乙烯基硼酸频哪醇酯或三丁基乙烯基锡试剂通过偶联反应制得中间体5；
(e)以中间体5为原料，在锇试剂及氧化剂的作用下制得中间体6；
(f)以中间体6为起始原料，与胺类化合物缩合及氰基硼氢化钠或三乙酰氧基硼氢化钠作用下制得通式I中的目标化合物。；
所述的R1、R2、R3、X、Y的定义如权利要求1～3所述，
6.一种药物组合物，所述药物组合物包含作为有效成分的权利要求1～4任一项所述的化合物及其立体异构体以及药学上可接受的盐、载体或赋形剂。
7.权利要求1～4任一项所述化合物及其立体异构体以及药学上可接受的盐，或权利要求6所述的药物组合物在制备预防和/或治疗与PD-1/PD-L1信号通路异常有关疾病的药物中的应用。
8.根据权利要求7所述的应用，与PD-1/PD-L1信号通路异常有关的疾病选自癌症、感染性疾病、自身免疫性疾病。
9.根据权利要求7所述的应用，所述的癌症选自淋巴瘤、非小细胞肺癌、小细胞肺癌、头颈部细胞癌、神经胶质瘤、成神经细胞瘤、肺鳞癌、肺腺癌、膀胱癌、胃癌、结肠癌、大肠癌、肾癌、胆管癌、胃癌、食管鳞癌、卵巢癌、胰腺癌、乳腺癌、前列腺癌、肝癌、脑癌、黑色素瘤、多发性骨髓瘤、皮肤癌、上皮细胞癌、白血病和宫颈癌；所述的感染性疾病选自细菌感染、病毒感染；所述的自身免疫性疾病选自器官特异性、系统性自身免疫病。其中，所述器官特异性自身免疫病包括慢性淋巴细胞性甲状腺炎、甲状腺功能亢进、胰岛素依赖型糖尿病、溃疡性结肠炎、急性特发性多神经炎，所述的系统性自身免疫病包括类风湿性关节炎、系统性红斑狼疮、系统性血管炎、自身免疫性溶血性贫血。
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